Keynote Lecture: Cancer Treatment Induced Bone Loss

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Cancer Treatment Induced Bone Loss Fisiopatologia

Airoldi Mario S.C. Oncologia Medica 2 Città della Salute e della Scienza di Torino

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Il nuovo concetto di bone health nel paziente neoplastico

FRATTURE DA FRAGILITÀ

OSTEOPOROSI METASTASI OSSEA

SRE

 Fratture

 Radioterapia

 Compressione spinale

 Interventi ortopedici

 Dolore

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Il nuovo concetto di bone health nel paziente neoplastico

ELEVATO TURNOVER OSSEO

 Goserelin

 Chemioterapia

 Inibitori dell’aromatasi

 Elevati livelli di citochine (IL-1, IL-6, IL-12, TNF-α)

 Corticosteroidi

 Menopausa

 Invecchiamento

 Ipovitaminosi D/Elevati livelli di PTH

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Il rimodellamento osseo: l’unità di rimodellamento - BMU

TGF-β1 IGF-1 PDGFBMP FGFs

CROSS-LINK COLLAGENO

TIPO I APOPTOSI

CTX NTX DPD HOProl

β-ALP OC

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Turnover osseo

Turnover basso

Turnover medio

Turnover elevato ALP OC

NTX CTX ICTP

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N-TELOPEPTIDE

NTX sierico

N C

C-TELOPEPTIDE

GPP-SAGFDFSFLPQPPQEKAHDGGR α 1

I prodotti di catabolismo del collageno di tipo I (osseo) derivanti dall’attività riassorbitiva degli osteoclasti

Mod. da: Garnero P, et al. J Bone Miner Res 18: 859-867, 2003 Cat K Cat K Cat K

ICTP CTX

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NTX E CTX SIERICO

 NTX NORMALE < 50 nmol/mmolCr

 NTX INTERMEDI 50-100

 NTX ELEVATI > 100

 CTX NORMALE < 0,400 ng/mL

 CTX INTERMEDI 0,400-0,800

 CTX ELEVATI > 0,800

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FRATTURE DA FRAGILITÀ OSTEOPOROSI

METASTASI OSSEA SRE

 Fratture

 Radioterapia

 Compressione spinale

 Chirurgia ortopedica

 Dolore

ELEVATO TURNOVER OSSEO

 Goserelin

 Chemioterapia

 Inibitori dell’aromatasi

 Menopausa

 Invecchiamento

 Ipovitaminosi D

Il nuovo concetto di bone health nel paziente neoplastico

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Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer

Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004

0 10 15 20 25 30 35 40

NTX nM BCE

ADT - Meta -

ADT + Meta -

ADT + Meta +

*

ns

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Osteoporosis Normal bone density Osteoporosis is asymptomatic, and it is associated to an increase in the risk of fractures due to minor traumas (falls from a height which is below one’s stature), but not due to more important traumas (road accidents, falls from heights above one’s stature).

Osteoporosis and risk of fractures

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Mechanism of Bone Loss: Estrogen Dependence of Bone Health in Both Women and Men

Schematics adapted from Kawano et al. Proc Natl Acad Sci. USA. 2003;100: 9416-9421; 1. Riggs et al. Endocrine Rev.

2002;23:279-302; 2. Khosla et al. Calcif Tissue Int. 2001;69:189-192; 3. Smith et al. J Clin Endocrinol Metab. 2002;87:

599-603.

Sex hormone depletion by androgen deprivation (ADT) or aromatase inhibitors (AI) leads to estrogen deficiency, resulting in deleterious bone effects^1-3

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Potential roles of osteoclast- targeting agents in breast cancer

Preventing recurrence and

deaths?

Preserving bone mineral density, preventing fractures

Treating bone metastases, reducing skeletal- related events

Adjuvant setting Metastatic setting

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Normal Osteoporotic Osteoporosis and Bone Density

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Cancer Treatment–Induced Bone Loss

 Rapid and severe bone loss resulting from cancer

therapies that lead to estrogen or androgen deprivation

 Various cancer therapies decrease BMD and increase fracture risk

• Androgen-deprivation therapy

• Estrogen-deprivation therapy

• Chemotherapy

• Surgical (castration)

 CTIBL has significant clinical, social, and economic

consequences; treatment-related fractures are associated with decreased quality of life and shorter survival

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Oestrogen and bone loss

Oestrogen plays a key role in bone loss caused by hormone ablation therapy (testosterone is converted to oestrogen by aromatase)

ADT causes a reduction in

testosterone, therefore suppressing oestrogen levels

Low oestrogen levels lead to reduced production of OPG and increased RANK Ligand production by

osteoblasts

Increased levels of free RANK Ligand lead to osteoclast activation and

increased bone resorption

Increased bone resorption leads to a loss of BMD and an increased risk of fracture

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The effects of suppressed oestrogen levels on bone loss

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CTIBL-AD caused by ADT

ADT

T TT



 



  

Oe Oe Oe

T Testosterone  Prostate cancer cell Oe Oestrogen

ADT significantly suppresses androgen

production, which suppresses tumour

growth

ADT shuts down oestrogen production, which causes significant bone loss and increased

risk of fracture

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Key Slides on La bone health nel paziente neoplastico

Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer

0 10 15 20 25 30 35 40

NTX nM BCE

Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004 ADT -

Meta -

ADT + Meta -

ADT + Meta +

*

ns

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18

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Bone Loss Induced by ADT for Prostate Cancer Is Clinically Significant

(N not available for 2 left bars)

1. Adapted from Hirbe et al. Clin Cancer Res. 2006;12(20 Pt2):6312s-6314s; 2. Michaelson et al. J Clin Oncol.

2007;25:1038-1042; 3. Eastell et al. J Bone Miner Res. 2002;17:S165. Abstract 1170.

Healthy Men¹ Early Menopausal

Women1

Women on Aromatase Inhibitor Therapy³

n = 308

Men After 1 Year of ADT²

n = 22

Lumbar Spine BMD Loss at 1 Year (%)

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ADT Effects on BMD in Men with PCa:

Pronounced Decreases Are a Consistent Finding

Study Treatment BMD (% decrease at 12 mo)

Eriksson¹ Orchiectomy Hip: - 9.6% Radius: - 4.5%

Maillefert² GnRH agonist Hip: - 3.9% L spine: - 4.6%

Daniell³ Orchiectomy or GnRH agonist Hip: - 2.4%

Berrutti⁴ GnRH agonist Hip: - 0.6% L spine: - 2.3%

Higano⁵ LHRH agonist plus anti-androgen Hip: - 2.7% L spine: - 4.7%

Mittan⁶ GnRH agonist Hip: - 3.3% Radius: - 5.3%

1. Eriksson et al. Calcif Tissue Int. 1995;57:97-99; 2. Maillefert et al. J Urol. 1999;161:1219-1222;

3. Daniell et al. J Urol. 2000;163:181-86; 4. Berrutti et al. J Urol. 2002;167:2361-2367;

5. Higano et al. Proc Am Soc Clin Oncol. 1999;18:314a; 6. Mittan et al. J Clin Endocrinol Metab. 2002;87:3656-3661.

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Bone Loss With Cancer Therapies

1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Mineral Res. 2002. 3. Maillefert JF, et al.

J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.

Bone Loss at 1 Yr

Naturally Occurring Bone Loss

CTIBL

0 2 4 6 8 10

Normal Men^[1]

Postmenopausal Women^[1]

Menopausal Women^[1]

Al Therapy in Postmenopausal

Women^[2]

ADT^[3]

Al Therapy + GnRH Agonist in Premenopausal Women^[4]

Premature Menopause Secondary to Chemotherapy^[5]

0.5 1.0

2.0 2.6

4.6

7.0 7.7

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Measuring bone loss

• Changes in bone mineral density (BMD)

• Bone density classified using T- Score

• DXA (dual energy X-ray absorptiometry) is the most

accurate and widely used technique for measuring BMD, and typically involves evaluating BMD of the spine and/or hip

Bone loss in prostate cancer

 Why do bone complications occur in patients with prostate cancer?

 Metastases

 As a result of the cancer treatment (CTIBL)

 Cancer treatment-induced bone loss (CTIBL) is particularly associated with:

 Prostate cancer (CTIBL-AD)

 Breast cancer (CTIBL-AI)

 WHY?

 Because treatment often includes hormone ablation that may interfere with normal bone metabolism

Classification T-Score

Normal -1 or greater

Low bone mass

(osteopenia) Between -1 and -2.5 Osteoporosis -2.5 or lower Severe (established) -2.5 or lower plus a

fragility fracture

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 ADT also increases fracture risk, with 1 in 5 prostate cancer patients receiving multiple doses of ADT experiencing a fracture within 4 years of diagnosis

 CTIBL-AD has very few symptoms, and is not usually detected until a fracture occurs

 ADT drops oestrogen to even lower levels than those found in

postmenopausal women

 BMD loss of up to 4.6% has been reported in the first year of ADT

treatment in prostate cancer patients without metastases; this slows down over time to a steady state

 ADT is associated with increased fracture risk

CTIBL-AD caused by ADT: evidence

CTIBL bone loss vs normal bone loss

ADT-related fracture risk in prostate cancer

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100 90 80 70 60 50 40 30 20 10

1 2 3 4

NTX nmol/mmol Cr

Meta - Meta + Breast cancer

AI

1. Coleman RE, et al. J Clin Oncol. 23: 4925–4935, 2005 2. Eastell R,et al. J Bone Min Res 2: 1215–1223, 2006 3. Coleman RE, et al. Lancet Oncol 8: 119–127, 2007 4. Gonnelli S, et al. Bone 40: 205–210, 2007

Bone turnover in breast cancer patients with or without bone metastases

Normal range

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Tamoxifen

Letrozole Anastrozole

Fractures (%)

11.0

7.7

5.7 4.0

7.0 5.0

P < .0001

P < .001

0 2 4 6 8 10 12 14

P = .003

Exemestane

ATAC^[1]

(68 Mos) IES^[2]

(58 Mos) BIG 1-98^[3]

(26 Mos)

Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen

1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127.

3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757.

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In the ATAC trial, after 2 yrs of anastrozole treatment, BMD decreased at lumbar spine (median loss: 4.1%) and total hip (median loss: 3.9%)^[6]

BMD increases of 2.2% and 1.2% were observed with tamoxifen in lumbar spine and total hip, respectively^[6]

1. Howell A, et al. Lancet. 2005;365:60-62. 2. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757.

3. Coombes RC, et al. ASCO 2006. Abstract LBA527. 4. Jakesz R, et al. Breast Cancer Res Treat.

2004;88:S7. Abstract 2. 5. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271. 6. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223.

Adjuvant Studies With AIs in Breast Cancer:

Increased Fracture Rate

N Median F/U, Mos

Aromatase Inhibitor, %

Tamoxifen, % P Value

ATAC^[1] 6186 68 11.0 ^7.7 ^{< .0001}

BIG 1-98^[2] 8010 26 5.8 ^4.1 ^.0006

IES^[3] 4724 56 7.0 4.9 .003

ARNO^[4] 3224 28 2.4 1.2 NR

Placebo %

MA.17^[5] 5187 30 5.3 ^4.6 ^.25

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AI-induced estrogen deficiency



The AIs are divided into steroidal inactivators

(exemestane) and nonsteroidal inhibitors (letrozole, anastrozole).

 At clinical doses, these third-generation AIs are successful in inhibiting greater than 97 percent of aromatase activity in vivo .

27

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…AI-induced estrogen deficiency

 In vivo animal studies suggest that exemestane may be more bone sparing than letrozole, owing to its androgenic structure .

 However, there are no human trials showing a differential effect of the individual AIs on bone.

 The MA-27 trial is a comparative trial of exemestane versus

anastrozole as adjuvant therapy in postmenopausal women. The results are likely to provide more conclusive information about the skeletal effects of the steroidal versus nonsteroidal AIs.

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Effect of AIs on bone loss

 Having a postmenopausal status is a risk factor for increased bone loss

 Use of AIs is an additional risk factor

• AI use is associated with a BMD loss that is 2-3% more per year than the normal decrease in BMD seen in postmenopausal women

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A 44% increase in relative risk of fracture with the AI anastrozole was reported from a trial comparing

anastrozole with tamoxifen

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Cancer Treatment Induced

Bone Loss

Epidemiologia

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Incidence of menopause in breast cancer patients

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Osteoporosis – Incidence in Breast Cancer Patients

• Women’s Health Initiative-observational Study (5.000 Breast Cancer Patients and 80.000

Controls)

• Breast Cancer survivors had a 28% increased risk of non hip fracture after adjustment for age, weight, length of menopause

Chen Z et al; Arch Intern Med 2005; 165:552-558

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Annual Incidence (%) and severity (±SEM) of vertebral fractures in controls and

Breast Cancer Patients

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EPIDEMIOLOGIA DEL CANCRO DELLA MAMMELLA E DELL’UTILIZZO DEGLI INIBITORI DELL’^AROMATASI (^IA)

In ITALIA 38.000 donne / anno si ammalano di cr della mammella.

200 nuovi casi/100.000 donne oltre i 50 anni (AIRTUM 2011)

L’85% sopravvive a 5 anni (89-90% al Nord/ 81-83% Sud) (AIRTUM 2011)

Il 40% circa inizia IA. La durata della terapia con IA è per 5 anni Nel 2010 vi erano 125.000 donne in terapia con IA ( OSMED 2010)

Considerando l’incidenza di fratture negli RCT con IA tra 5-11%, si Possono stimare nel 2010 tra 6.000 e 14.000 pazienti con fratture da fragilità.

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TSE: 149/100.000 persone / anno

PROSTATE CANCER EPIDEMIOLOGY

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Conti G , Dogliotti et al , Eur Soc Med Oncol 2008

EPIDEMIOLOGIA DELL’ UTILIZZO DEL BLOCCO ORMONALE ADIUVANTE

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In breast cancer:

Survival improvement has necessitated refocus on

preserving patients overall health , functional autonomy ,and quality of life throughout the extended disease course.

Fracture risk is elevated in patients with newly diagnosed

breast cancer compared with age – matched women without breast cancer , and breast cancer itself as well as long –

term adjuvant therapies for this disease may further increase the risk of fractures.

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SKELETAL OUTCOMES

 Bone loss is most rapid in pre-menopausal women receiving both ovarian suppression therapy (GnRH agonist) and an AI.

As a consequence, the risk of fracture is substantially increased

Fractures may ↑ mortality, DVT

↓ QoL, Mobility

(39)

Some chemotherapeutic agents may directly affect bone , resulting in a rapid decrease in BMD; however , indirect effects of chemotherapy may also result in rapid BMD decline.

For example, ovarian dysfunction is common with chemotherapy in premenopausal women, leading to premature menopause.

Bone health during adjuvant therapy for early breast cancer